Role of bradykinin and tachykinins in the potentiation by enalapril of coughing induced by citric acid in pigs

Angiotensin-converting enzyme (ACE) inhibitors are among the first-choice d rugs for treating hypertension and congestive heart disease. It has been re ported, however, that these drugs could induce chronic cough and airway hyp erresponsiveness, The aim of this work was to assess in pigs the effects of bradykinin and tachykinins on citric-acid-induced coughing after ACE inhib itor pretreatment, Coughing was induced by challenging pigs with an aerosol , of 0.8 M citric acid over 15 min, Coughs were counted by a trained observ er for 30 min. The animals underwent two cough induction tests two days apa rt (days 1 and 3), the first being taken as a control. All drugs were injec ted intravenously 30 min before the second challenge. In the control group, no difference was observed between days 1 and 3, The ACE inhibitor enalapr il (7.5 and 15 mug/kg) caused the cough frequency to increase significantly . In contrast, a dose-related decrease was observed with Hoe140 (icatibant) , a bradykinin B2 receptor antagonist (0.5 and 1 mg/kg), When both drugs we re administered simultaneously (15 mug/kg for enalapril and 1 mg/kg for Hoe 140), a significant increase was observed as compared with the control valu e obtained on day 1. When enalapril was combined with the three tachykinin receptor antagonists SR 140333 (NK1 receptor antagonist), SR 48968 (NK2 rec eptor antagonist) and SR 142801 (NK3 receptor antagonist), a significant de crease was observed as compared with control value obtained on day 1; the p ercentage of variation was also significantly different as compared with th ose observed in enalapril groups at both doses, These data suggest that ACE -inhibitor-induced enhancement of the cough reflex is mainly due to tachyki nins and not to bradykinin in our pig model, Bradykinin, however, plays a m ajor role in coughing induced by citric acid alone.